IL4 and IL13 are related cytokines that show a significant sequence identity [1,2] and share numerous biological activities. Both have been shown to be important in the induction of IgE and IgG4 synthesis in human B cells [3-6] and the differentiation of Th cells into a Th2 phenotype [8,11]. Among the events leading to IgE synthesis by B cells, induction of germline .epsilon. RNA transcription, which precedes the class switching to the corresponding H chain C region, has been shown to be triggered by IL4 and IL13 [6,9,10]. Th cells can be subdivided into two major subtypes according to their cytokine production capacities [11]. The major distinction between the two phenotypes are the capacity of Th1 cells to secrete IFN.gamma. and Th2 cells to produce IL4 and IL5 [11]. Th2 cells are thought to be implicated in the development of atopy, allergy and some forms of asthma [12,13]. The differentiation of Th cells into the Th2 phenotype can be induced by IL4 [11]. IL13 was first considered as to be inactive on T cells [2]. However it has been shown recently to induce the differentiation of murine Th cells into the Th2 phenotype [8].
In addition to their effects on lymphocytes, IL4 and IL13 share the ability to inhibit the production of inflammatory cytokines by macrophages [1,2] and to up-regulate the expression of the vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells [16,17,18] leading to adhesion and trans-endothelial migration of very late antigen 4 (VLA-4) expressing leukocytes [19]. This provides a basis for selective extravasation of eosinophils, the hallmark of the inflammatory pathology seen in allergy and asthma [20,58,59].
These two cytokines activate common cytokine receptor signaling pathways involving 4PS/IRS-1 [21-25] and the signal transducer and activator of transcription 6 (STAT-6; ref. 26-28). In the murine system, inactivation of STAT-6 has been demonstrated to affect both IL4 and IL13 signaling and to block IL4 and IL13-induced IgE synthesis or Th2 differentiation [29-31].
Studies have been conducted to examine if these two cytokines share a receptor or receptor subunits [2,18,32-34]. The IL4R is composed of two chains, the IL4R.alpha. chain and the common .gamma. chain (.gamma..sub.c). The .gamma..sub.c is shared with the receptors of many of the other 4-helix bundle cytokines such as IL2, IL4, IL7, IL9 and IL15 [35,36]. The IL4R.alpha. chain alone forms a tight complex with its ligand, whereas the .gamma..sub.c was thought to be mainly responsible for signal transduction. However, IL4- and IL-3-induced responses could be observed in cells which naturally do not express .gamma..sub.c or in lymphocytes obtained from severe combined immunodeficiency (SCID) patients who are deficient for .gamma..sub.c [34,37-39]. It has therefore been proposed that a second form of an IL4R exists which would be activated by both IL4 and IL13 (IL4R type II/IL13R; ref. 40).
A cDNA encoding for a human IL-13 receptor .alpha. chain (IL-13 R .alpha.) has been cloned (Caput et al [42]). IL-13 R .alpha. has been shown to participate in the type II IL-4 receptor which also contains an IL-4 R .alpha. chain.